HIV infection leads to progressive deterioration of the immune system in most infected subjects. This infection frequently leads to an immune system dysfunction which may culminate in AIDS, a syndrome characterized by the development of opportunistic infections and cancer (Levy, 1993, Microbiol. Rev., 57:183-289). Cells infected with HIV include, e.g., CD4+ T cells, macrophages/monocytes, dendritic cells, and glial cells. The immune system in late stages of AIDS is severely compromised due to loss or dysfunction of CD4+ T cells (Shearer et al., 1991, AIDS, 5:245-53), macrophages, monocytes, and dendritic cells. (Rosenberg et al., 1989, Adv. Immunol., 46:377).
Anti-retroviral drugs, such as reverse transcriptase inhibitors, viral protease inhibitors, and viral entry inhibitors have been used to treat HIV infection. (Caliendo et al., 1994, Clin. Infect. Dis., 18:516-24). These treatments can effectively suppress viral production when used in combinations known as HAART (highly active anti-retroviral therapy). However, they are mainly effective in preventing new infection of uninfected cells. They are generally far less effective in eliminating latent virus from infected cells. Even after two years on HAART, HIV-1 can still be induced, and viral production resume when HAART is stopped (Finzi et al., 1997, Science, 278:1295-1300; Wong et al., 1997, Science, 278:1291-1295). Hence, HAART likely needs to be continued indefinitely. This poses significant difficulties. HAART regimens have many side effects, are difficult to comply with, and are expensive. Moreover, prolonged treatment with these drugs often leads to the emergence of drug resistant viral strains (Larder et al., 1989, Science, 246:1155-8; Kellam et al., 1992, Proc. Nat'l. Acad. Sci. USA, 89:1934-8; St. Clair et al., 1991, Science, 253:1557-9). Combination therapies entailing treatment with two or more drugs which attack different points in the HIV replication cycle delay the emergence of resistant HIV strains. (D'Aquila, 1994, Clin. Lab. Med., 14:393:422). However, recent data suggest that HIV strains having multi-drug resistance may eventually develop in a significant portion of patients treated with combination therapy. (Schinazi et al., 1994, Int. Antiviral News, 2:72-5).
Many other important infectious pathogens can exist in a latent state where they are dormant or replicate very slowly. Examples of these pathogens include retroviruses, e.g., human immunodeficiency virus type 2 (HIV-2), human T lymphotropic virus type 2 (HTLV-2); herpesviruses, e.g., Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), herpes zoster virus (HZV), herpes virus type 6 (HHV-6), herpes virus type 7 (HHV-7); hepatitis viruses, e.g., hepatitis B (HBV), hepatitis C (HCV), the delta agent, and hepatitis E, mycobacteria, e.g., M. tuberculosis (MTB), M. avium (MA), M. Leprae; and fungal agents e.g., histoplasmosis, coccidiomycosis, cryptococcus, and pneumocystis. Keeping the infectious pathogen in latency is desirable when there is no available therapy. However, in many cases, the pathogen is not completely latent and therapy is required. Unfortunately, while active infection can often be contained by therapy, it is difficult or impossible to attack latent pathogen. Moreover, latent infection can give rise to renewed production of the infectious microbes when the anti-viral/anti-microbial agents are stopped.
HIV-2 can cause immunodeficiency similar to HIV-1. HTLV-1 has been shown to cause T cell lymphoma. EBV may cause lymphoma and other lymphoproliferative diseases. CMV may cause retinitis, hepatitis, pneumonitis, and other systemic illness, especially in immunocompromised host. HSV 1 and 2, and Herpes Zoster (HZV) can cause painful vesicles at the area of infection and occasional meningitis. HHV-6 has been demonstrated to be present in and may contribute to the pathogenesis in certain subgroups of patients with multiple sclerosis and chronic fatigue syndrome. Nucleoside analogs such as ganiclovir, famciclovir, lamivudine, and ribavirin have been shown to be effective against many of these infections. These drugs interfere with viral replication, but they generally cannot attack latent virus. Hence, viral replication often resumes when the drugs are withdrawn.